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Pharmacological Approaches to Pediatric Mania
JANET WOZNIAK, MDAssociate Professor of PsychiatryHarvard Medical SchoolChair, Quality and Safety, Department of PsychiatryDirector, Child and Adolescent Outpatient Psychiatry ServiceDirector, Pediatric Bipolar Disorder Clinical and Research ProgramAssociate Director, Bressler Clinical and Research Program for Autism Spectrum DisordersMassachusetts General HospitalBoston, Massachusetts
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My spouse/partner and I have the following relevant financial relationships with commercial interests to disclose:
For Janet Wozniak MD• Research support: PCORIAuthor: “Is Your Child Bipolar” published May 2008, Bantam Books.
• Spouse royalties: UpToDate• Spouse consultation fees: Advance Medical, FlexPharma,
Merck, Otsuka and Gerson Lehman Group• Spouse research support: RLS Foundation
Pediatric Bipolar Disorder: Advances in Treatment for Clinical Practice
Janet Wozniak, MDDirector, Pediatric Bipolar Disorder Research Program
Associate Professor of Psychiatry
Harvard Medical School
Massachusetts General HospitalIncreasing numbers of treatment trials
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Overview: Pediatric Bipolar disorder is a highly morbid condition that
usually requires pharmacologic treatment due to severity of illness. SGA’s are the first line of treatment and comorbid conditions usually must be addressed.
Severity: Pediatric Bipolar Disorder is associated with suicidality, substance addiction and conduct disorder
Treatment: Pharmacologic treatment is generally required and SGAs are the first line of treatment
Comorbid Conditions: ADHD and depression and anxiety can be treated by sequencing appropriate treatments after the mania is stabilized
Natural Treatments: Complementary and alternative treatments hold promise for safe treatment and prevention
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The symptoms of mania are the same in children and adults with presentations appropriate to developmental stage
A. A distinct period of abnormally and persistently elevated, expansive or irritable mood and persistently increased goal-directed activity or energy
B. At least 3/7 (4/7 if mood is irritable)1) D Distractibility2) I Increased activity/psychomotor agitation 3) G Grandiosity or inflated self-esteem4) F Flight of ideas or racing thoughts5) A Activities with painful consequences6) S Sleep decreased7) T Talkative or pressured speech
Diagnostic and Statistical Manual (DSM-5)
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We have many FDA approved treatments for youth with emotional dysregulation
Lithium: manic or mixed states, patients age 13-17
Risperidone: manic or mixed states, age 10-17Aripiprazole: manic or mixed states, age 10-17Olanzapine: manic or mixed states, age 13-17Quetiapine: monotherapy or adjunct to lithium or divalproex sodium, manic states, age 10-17Saphris manic or mixed episodes in BPD I, age 10-17
Fluoxetine: depression and OCD age 8+Escitalopram: depression age 12+Sertraline,fluvoxamine, anfranil: pediatric OCD
Aripiprazole: irritability associated with autistic disorder age 6-17Risperidone: irritability associated with autism age 5-16
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SUICIDE
ADDICTION
CRIMINAL ARREST
POOR JUDGMENT
The risk-benefit analysis of treatment must include the risks associated with not treating Bipolar Disorder
FinancialSexualDaredevil risks
Delaying treatment could lead to worse outcomes
Post, Leverich 2010
Both childhoodonset and treatment delay were associated with a
persistently more adverse course of illness
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Perlis, Biol Psych 2004;55:875-881
N=983983 bipolar adult participants
Not treating is not an option due to the severity of symptoms associated with early onset bipolar disorder
Year 1900-2000
20TH-CENTURY - RISING RATE OF SUICIDE IN YOUTHU N I T E D S T A T E S , A G E S 15–24
Rat
e p
er
10
0,0
00
GIRLS3X AS MANY ATTEMPTS
Bipolar adults with pediatric onset have more lifetime suicide attempts
BOYS5X AS MANY COMPLETED SUICIDES
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The algorithm for pediatric bipolar disorder pharmacologic treatment is general
Stage I – monotherapy +/- augmentation
Stage 2 – switch monotherapy agent
Stage 3 – combination mood stabilizer + SGA (Or switch monotherapy agent)
Stage 4 – combination 1 mood stabilizer + SGA 2 mood stabilizers + SGA
Stage 5 – alternate monotherapy
Stage 6 – ECT vs. Clozapine
Kowatch JAACAP 2005
SGA=second generation antipsychotic
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50% of adults and adolescents with mania require augmentation with another
agent/combination therapy
Kowatch 2003, 2005
Pediatric bipolar disorder is difficult to treat
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Many subjects have participated in pediatric anti-manic trials
J Am Acad Child Adolesc Psychiatry, 2011;50(8):749-762
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The mean decrease in YMRS in pediatric studies is much greater for the SGAs than for other agents
-10.99 -11.03
-16.8
-5.6
-18
-16
-14
-12
-10
-8
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-2
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Traditional MoodStabilizers
OtherAnticonvulsants
AtypicalAntipsychotics
NaturopathicTreatments
YM
RS S
core
Liu JAACAP 2011
SGAs are more effective than placebo in available trials• Perform well in open label – 80+%• Mean response rate of ~60% drug vs. 20-30%
placebo • Mean decrease in YMRS ranged from 14.2 to 18.5
in medication group vs. 8.2 to 9.99 for placebo• Relatively rapid response, relatively well tolerated
SGA=second generation antipsychotic
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aripiprazole 70%
Liu JAACAP 2011;50(8):749-762
aripiprazole 70%
Response Rates (50%+ decrease in YMRS) Open Label Trials
YMRS=Young Mania Rating Scale
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aripiprazole 70%
risperidone 52%olanzapine 51%quetiapine 45%
Liu JAACAP 2011;50(8):749-762
aripiprazole 70%
risperidone 52%
olanzapine 51%
quetiapine 45%
Response Rates (50%+ decrease in YMRS) Open Label Trials
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aripiprazole 70% risperidone 52%olanzapine 51%quetiapine 45%
ziprasidone 33%
Liu JAACAP 2011;50(8):749-762
aripiprazole 70%
risperidone 52%
olanzapine 51%
quetiapine 45%
ziprasidone 33%
Response Rates (50%+ decrease in YMRS) Open Label Trials
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aripiprazole 70% risperidone 52%olanzapine 51%quetiapine 45%ziprasidone 33%
omega-3 35%
Liu JAACAP 2011;50(8):749-762
aripiprazole 70%
risperidone 52%
olanzapine 51%
quetiapine 45%
ziprasidone 33%
omega-3 35%
Response Rates (50%+ decrease in YMRS) Open Label Trials
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aripiprazole 70% risperidone 52%olanzapine 51%quetiapine 45%ziprasidone 33%
omega-3 35%
Liu JAACAP 2011;50(8):749-762
aripiprazole 70%
risperidone 52%
olanzapine 51%
quetiapine 45%
ziprasidone 33%
valproic acid 22%
omega-3 35%
Response Rates (50%+ decrease in YMRS) Open Label Trials
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SGAs are a robust treatment for adults with bipolar disorder
Perlis J Clin Psychiatry 2006; 64(4):509-516
SGA=second generation antipsychotic
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Tardive dyskinesia is dreaded, but low risk (although data limited by small sample sizes, low doses and limited durations)
0% children
0.8% adult
6.8% adult and elderly
5.4% adults haloperidol
Correll AmJPsych 2004
There is a lowerrisk for tardive dyskinesia associated with SGAs versus first generation antipsychotics
The weighted mean annual incidence of tardive dyskinesia for second generation antipsychotics (SGA):
• N=2769 • 11 studies • 1+year
first generation?
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Unfortunate weight gain noted in 8-week open label trials of SGA monotherapy in children with bipolar disorder
00
01
02
03
04
05
06
0 1 2 3 4 5 6 7 8
Ch
an
ge f
rom
Baselin
e (
kg
) olanzapine
ziprasidone
quetiapinerisperidonearipiprazole
Biederman 2007 AACAP Boston
weeks
SGA=second generation antipsychotic
Parallel trialsTotal N=116
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Weight gain associated with SGA medications in children and adolescents: Data from 34 studies
3.8 to 16.2 kg olanzapine n=353
0.9 to 9.5 kg clozapine n=97
1.9 to 7.2 kg risperidone n=571
2.3 to 6.1 kg quetiapine n=133
0 to 4.4 kg
aripiprazole n=451
Correll JChildAdolescPsychopharm 2011
SGA=second generation antipsychotic
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Lithium, divalproex sodium, carbamazepine can be used for pediatric bipolar disorder but are not as effective as SGAs
53% 38% 38%
Kowatch JAACAP 2000
RESPONSE RATES FAIR
divalproex sodium lithium carbamazepine
Trials notable for:
• high drop out rates
• need for rescue medications
SGA=second generation antipsychotic
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Lithium has long been FDA-approved for pediatric bipolar disorder, but the first double blind RCT study for pediatric BP-I was in 2015
Findling Pediatrics 2015
47% lithium vs 21% placebo “much/very much improved”
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SGAs perform better than valproate for pediatric bipolar disorder
Chen 2014
SGA=second generation antipsychotic
more rapid onset of effect
greater reduction of
manic symptoms
3 double blind RCTs
1 chart review
second generation antipsychoticsvalproate versus
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Comparable risk of psychiatric hospital admission
186 days
Patients who initiated on SGA were less likely to discontinue the treatment
Patients who initiated on SGA were less likely to receive treatment augmentation
Chen 2014
SGAs performed better than mood stabilizers with less discontinuations and less need for augmentation
N=7423mean age 12.7357% adolescents 54% males
66.60% SGA 33.40% mood stabilizer(valproate/oxcarbazepine/lithium)
Retrospective Medicaid claims study of pediatric bipolar disorder
patients who initiated a new treatment episode for bipolar disorder
on either an SGA or mood stabilizer, followed for 12 months
SGA=second generation antipsychotic
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Newer mood stabilizers hold promise for the treatment of mania in children with bipolar disorder
Prospective open-label trial of
lamotrigine
monotherapy
Prospective open-label trial of
extended-release carbamazepinemonotherapy
Joshi 2010
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Depression
Lithium, Lamotrigine, Lurasidone
Avoid SSRIs
ADHD
Employ stimulant after mood stabilized
Anxiety
Avoid SSRIs
Joshi 2009
Comorbidity must be addressed in addition to mania
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Euthymic youths with bipolar disorder and ADHD may benefit from concomitant treatment with methylphenidate
Findling 2007
4-week double-blind placebo-controlled
ages 5-17
Bipolar disorder and ADHD
Anti-manic medication
Euthymic
Clinically significant symptoms of ADHD
1 week each of
placebo methylphenidate
5 mg BID
10 mg BID
15 mg BID
Crossover design randomly assigned to one of six possible dosing orders
Therapeutic benefit
Lower ADHD Rating Scale scores during best dose treatment vs placebo
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Euthymic youths with bipolar disorder and ADHD may benefit from concomitant treatment with methylphenidate
Findling 2007
4-week double-blind placebo-controlled
ages 5-17
Bipolar disorder and ADHD
Anti-manic medication
Euthymic
Clinically significant symptoms of ADHD
1 week each of
placebo methylphenidate
5 mg BID
10 mg BID
15 mg BID
Crossover design randomly assigned to one of six possible dosing orders
Therapeutic benefit
Lower ADHD Rating Scale scores during best dose treatment vs placebo
Fully mood stabilized, low dose stimulant, short term
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Amphetamine Salts provided therapeutic benefit versus placebo in a double-blind crossover trial of pediatric bipolar disorder and ADHD
Scheffer 2005
p<0.001
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Amphetamine Salts provided therapeutic benefit versus placebo in a double-blind crossover trial of pediatric bipolar disorder and ADHD
Scheffer 2005
Fully mood stabilized, low dose stimulant, short term
p<0.001
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Treatment of ADHD in patients with bipolar disorder is feasible in the context of anti-manic treatment
Swedish national registries 2006-14
N=2,307
Adults with bipolar disorder who initiated therapy with methylphenidate
TWO GROUPS
Those WITHconcomitant mood-stabilizing treatment
Those WITHOUTconcomitant mood-stabilizing treatment
Treatment emergent mania:
Hospitalization
New mood stabilizing medication
No association between methylphenidate and treatment-emergent mania among bipolar patients who were concomitantly receiving a mood-stabilizing medication
Viktorin 2017
Determine the risk of treatment-emergent mania associated
with methylphenidate in patients with bipolar disorder
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Treatment of ADHD in patients with bipolar disorder is feasible in the context of anti-manic treatment
Swedish national registries 2006-14
N=2,307
Adults with bipolar disorder who initiated therapy with methylphenidate
TWO GROUPS
Those WITHconcomitant mood-stabilizing treatment
Those WITHOUTconcomitant mood-stabilizing treatment
Treatment emergent mania:
Hospitalization
New mood stabilizing medication
No association between methylphenidate and treatment-emergent mania among bipolar patients who were concomitantly receiving a mood-stabilizing medication
Viktorin 2017
Determine the risk of treatment-emergent mania associated
with methylphenidate in patients with bipolar disorder
Rule out bipolar disorder before initiating
methylphenidate as a monotherapy
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Treatment for bipolar disorder involves antipsychotic medications with side effects, fueling reluctance to diagnose
Traditional antidepressants should be avoided … treatment with a combination of atypical antipsychotics and mood stabilizers is best
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N-acetylcysteine currently in testing for pediatric bipolar disorder is a safe alternative
Complementary and alternative treatments may be especially useful for the earliest symptoms and the youngest children
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This positive result for omega-3 fatty acids is about 50% what we see with antipsychotics, but without the side effects
Wozniak, European Neuropsychopharmacology, 2007
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Funding/support: This study was supported by a generous philanthropic donation from Kent and Elizabeth Dauten (Chicago, Illinois).
November 2015
Advances in safe biologic treatments will encourage early identification
A novel study design of very young children allows all to receive treatment, but randomized and treated blindly
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The combined treatment of omega-3s and inositol outperformed either treatment used alone for mania
Wozniak, J Clinical Psychiatry 2015
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The combined treatment of omega-3s and inositol outperformed either agent used alone for depression
Wozniak J Clinical Psychiatry 2015
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The next generation of clinical trials can use technology to improve recruitment and access to care
Recruitment for clinical trials is difficult due to the burden of many in-person visits
Abrams…Wozniak, Harvard Review of Psych, 2017
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Recruitment for clinical trials is difficult due to the burden of many rating scales and clinical interviews
The next generation of clinical trials can take advantage of advances in evidence-based assessments to improve identification and participation in research
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Overview: Pediatric Bipolar disorder is a highly morbid condition that
usually requires pharmacologic treatment due to severity of illness. SGA’s are the first line of treatment and comorbid conditions usually must be addressed.
Severity: Pediatric Bipolar Disorder is associated with suicidality, substance addiction and conduct disorder
Treatment: Pharmacologic treatment is generally required and SGAs are the first line of treatment
Comorbid Conditions: ADHD and depression and anxiety can be treated by sequencing appropriate treatments after the mania is stabilized
Natural Treatments: Complementary and alternative treatments hold promise for safe treatment and prevention
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